rs142328166

Positions:

• chr20-6085276-G-A
• chr20-6085276-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_017671.5(FERMT1):​c.1383C>T​(p.Tyr461=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,613,418 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: FERMT1 NM_017671.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.201

Genes affected

FERMT1 (HGNC:15889): (FERM domain containing kindlin 1) This gene encodes a member of the fermitin family, and contains a FERM domain and a pleckstrin homology domain. The encoded protein is involved in integrin signaling and linkage of the actin cytoskeleton to the extracellular matrix. Mutations in this gene have been linked to Kindler syndrome. [provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 20-6085276-G-A is Benign according to our data. Variant chr20-6085276-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 897836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.201 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00137 (209/152260) while in subpopulation AFR AF= 0.00481 (200/41556). AF 95% confidence interval is 0.00427. There are 1 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FERMT1	NM_017671.5	c.1383C>T	p.Tyr461=	synonymous_variant	12/15	ENST00000217289.9	NP_060141.3
FERMT1	XM_024451935.2	c.1383C>T	p.Tyr461=	synonymous_variant	12/15		XP_024307703.1
FERMT1	XM_047440259.1	c.1383C>T	p.Tyr461=	synonymous_variant	12/15		XP_047296215.1
FERMT1	XM_047440260.1	c.1098C>T	p.Tyr366=	synonymous_variant	11/14		XP_047296216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FERMT1	ENST00000217289.9	c.1383C>T	p.Tyr461=	synonymous_variant	12/15	1	NM_017671.5	ENSP00000217289	P1
FERMT1	ENST00000478194.1	n.343C>T		non_coding_transcript_exon_variant	4/7	1
FERMT1	ENST00000536936.1	c.*885C>T		3_prime_UTR_variant, NMD_transcript_variant	11/14	1		ENSP00000441063
FERMT1	ENST00000699095.1	c.1383C>T	p.Tyr461=	synonymous_variant	11/14			ENSP00000514127	P1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152144 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000414 AC: 104 AN: 251374 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135882

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000178 AC: 260 AN: 1461158 Hom.: 0 Cov.: 34 AF XY: 0.000171 AC XY: 124 AN XY: 726898

Gnomad4 AFR exome AF: 0.00532

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74444

Gnomad4 AFR AF: 0.00481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000340 Hom.: 2

Bravo AF: 0.00168

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	- -

Kindler syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 12, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.3
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142328166; hg19: chr20-6065923; COSMIC: COSV54092829;